Abstract
Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.
Highlights
Epstein–Barr virus (EBV) is a human oncogenic virus that infects >90% of the global population (Young et al, 2016)
We found that CXCL8 was upregulated in EBV-infected gastric carcinoma (GC) cells, and overexpression of CXCL8 derived from EBV-infected cells promoted vasculogenic mimicry (VM) formation in GC cells through the NF-kB signaling, suggesting that the CXCL8 might serve as a potential therapeutic target for EBV-associated gastric carcinoma (EBVaGC)
We showed that EBV-encoded lncRNA RPMS1 upregulated CXCL8 expression, which accelerated VM formation through promoting EBV-positive cells proliferation and migration
Summary
Epstein–Barr virus (EBV) is a human oncogenic virus that infects >90% of the global population (Young et al, 2016). EBV infection is associated with a range of lymphoid and epithelial malignancies, such as Burkitt lymphoma (BL), Hodgkin lymphoma (HL), nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), among others. Unlike NPC, which exhibits a striking geographic distribution, with high incidence rates in Southern China and Southeast Asia, EBVaGC shows no apparent geographic distribution (Young et al, 2016). About 10% of gastric carcinoma (GC) worldwide is associated with EBV (Murphy et al, 2009), and EBV plays an important role in the development of EBVaGC (Morales-Sanchez and Fuentes-Panana, 2017). EBV infection does not lead to malignant transformation of normal gastric epithelial cells (Yang et al, 2020), raising uncertainty about the causal role of EBV in gastric carcinogenesis
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